The Office of Generic Drugs (OGD) fully implemented Question-based Review (QbR) in 2007 with the broad goal of encouraging sponsors to include quality-by-design (QbD) principles in their product and process development and to communicate this knowledge in their submissions. In light of this goal, OGD outlined the following four major benefits that the QbR platform would bring to the chemistry, manufacturing, and controls (CMC) review process (1, 2):

This article will provide a CMC reviewer's assessment of how QbR has contributed to achieving these benefits. The author will identify the current approach's strengths and areas for improvement within OGD and for sponsors of abbreviated new drug applications (ANDAs). The assessment and recommendations are based on the author's experience reviewing more than 20 QbR applications submitted during the past two years. The applications covered various dosage forms, including numerous modified-release drug products.

Ensuring product quality

Of the 37 questions in the current QbR QOS template, about 14 critical questions, most of which come from Section 3.2.P.2, are designed to encourage the sharing of product design and development information not typically included under the old CMC review paradigm. These questions incorporate QbD principles into the CMC review process and result in the most significant changes in the approach to product development and documentation suggested in a QbR ANDA for the sponsor and the reviewer. That is not to say that some information in these areas was not provided by sponsors and evaluated by CMC reviewers under the old review format. This information, however, was often provided only in response to agency queries or to correct deficiencies. Also, under the old paradigm, submissions and reviews in these areas were highly variable, thus no consistent basis for assessing process and product understanding was established. The QbR format has provided the necessary framework for sponsors to provide this information consistently and for CMC reviewers to assess this information critically.

Typically, the product development information that answers the critical QbR questions is incorporated into the ANDA as a Pharmaceutical Development Report (PDR). Incorporating the PDR into the ANDA review process is the most significant change brought about by the QbR approach because this information was almost entirely excluded under the old approach. The PDR provides the means for a sponsor to demonstrate to the reviewer its level of process and product understanding and provide the crucial link between the process, control testing, and specification choices in the final product to the data obtained during development on experimental and pilot-scale lots. Without a high-quality PDR that addresses these key questions in a meaningful way, the QbR amounts to little more than format change rather than the mechanism for communicating process and product understanding it was intended to be.

As previously pointed out, some QbR applications are accompanied by answers to these critical questions and PDRs that lack substantive information (3). Contrary to the intent of the critical QbR questions, some submissions demonstrate that QbD principles did not guide product and process development from the beginning and that sponsors have continued to test rather than design quality into their products. On the other hand, many high-quality submissions have incorporated QbD principles and thus benefited both the reviewer and the sponsor.

To realize the full extent of possible benefits for review quality and efficiency, it is imperative that sponsors provide meaningful answers to all of the relevant critical questions and submit PDRs that give a full scientific basis for them. The best product-development reports currently provided by sponsors possess the following common attributes:

Clearly present experimental design and clearly link it to the corresponding CQAs or CPPs with scientific rationales.

Present data to demonstrate why individual unit operations, specifications, or process parameters are or are not critical.

Present data from pilot batches of failing or suboptimal formulations or processes, offer an analysis of the issues and problems, and explain how this knowledge led to the optimized formulation or process. This information is especially useful for evaluating complicated products such as modified-release dosage forms.

Most QbR submissions stop short of using a design-of-experiments approach, often associated with QbD, to perform an extensive, systematic exploration of process parameters. However, a small number of experiments on laboratory-or pilot-scale lots in which carefully chosen critical variables are explored across a limited range is extremely useful in demonstrating process and product understanding. The experience gained by sponsors preparing high-quality PDRs will be helpful as OGD prepares to incorporate full QbD elements in the future (3–5). This transition will be much easier for sponsors who consistently provide high-quality PDRs with meaningful information.